The neurotransmitters norepinephrine and acetylcholine regulate cardiac function through specific receptors on the sarcolemma. Interaction of ligands with these receptors results in alterations in the intracellular levels of cyclic nucleotides in the heart. A culture system for dissociated heart cells will be used to investigate questions regarding the relationships between ligand interaction with cell surface receptors, changes in intracellular cyclic nucleotide levels, and alterations of the rate at which heart cells beat. The effects of catecholamines and cyclic AMP on cell growth and differentiation will be studied. The temporal and concentration-effect relationships between agonist interaction at beta-adrenergic and muscarinic cholinergic receptors and changes in intracellular cyclic nucleotide levels will be examined. In one series of experiments the molecular basis for catecholamine-induced desensitization will be investigated. Another group of experiments will be carried out to examine the possible role of muscarinic cholinergic receptors in the regulation of the cardiac response to acetylcholine. The effects of thyroxine on beta-adrenergic receptor/adenylate cyclase system will be investigated in the cultured heart cell system.